TRATTO DALLA CONFERENZA : AIDS/ARC di SINTEL/SINTAGMA
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deterioration and death, Dr. Stansell says physicians can
consider treatment with fluconazole (400 mg/day), without an
initial course of amphotericin B. In the NIAID study, the
patients at low risk did well on either drug as initial therapy.
Regardless of the primary treatment, all PWA with CM must take
lifelong suppressive therapy to prevent relapse of the disease.
Another NIAID study (ACTG 026) has shown that fluconazole (200
mg/day) is superior to amphotericin B as suppressive therapy and
is considerably less toxic. Dr. Stansell therefore recommends
that all patients who complete initial treatment with either drug
use fluconazole (200 mg/day) as maintenance therapy.
Amphotericin B Lipid Complex (ABLC) for Cryptococcal Meningitis
ABLC is a new drug formulated with amphotericin B enclosed in
a lipid complex in much the same manner as the drug design for
TLC-G-65 (see above). Bristol-Myers Squibb is conducting Phase
II trials of ABLC in 120 people with cryptococcal meningitis at
15 U. S. medical centers. Interested physicians and patients may
call the NIAID clinical trial Hotline for trial location sites
and entry criteria (1-800-874-2572).
ABLC could eventually become an important drug for people with
cancer or AIDS. In laboratory and animal studies, ABLC has 8 -
20 times less toxicity than the standard form of amphotericin B.
This "safety margin" may allow use of higher doses of ABLC than
are possible with amphotericin B alone.
Bristol-Myers Squibb is also planning trials of ABLC in people
with disseminated candidiasis, invasive pulmonary aspergillosis
and other fungal infections common in cancer and organ transplant
patients. For more information, call Bristol-Myers Squibb at 1-
609-921-5615.
566C80 for PCP
As reported in earlier issues of BETA (April 1990, August
1990), 566C80 is a promising new treatment for Pneumocystis
carinii pneumonia (PCP). In animal studies, the drug shows
potent activity against the Pneumocystis organism and may be able
to completely eradicate it. 566C80 also has an extremely low
toxicity profile. In Phase I safety and dose ranging studies,
only 1 person experienced adverse side effects that included
nausea, vomiting, headache and rash. The drug is taken orally,
which makes it convenient and easy to administer.
A Phase I/II study by the NIAID has enrolled 22 people to test
the safety and efficacy of 566C80 in people with mild to moderate
PCP. Burroughs Wellcome is conducting a Phase III trial comparing
the drug's effectiveness to one of the standard PCP treatments,
TMP-SMX (Septra).
Because of the drug's promise in early studies, trials of
566C80 as a prophylactic treatment for PCP are also under way.
The drug's effectiveness as a prophylactic will be tested in
comparison to both aerosolized pentamidine and Septra. For more
information about open trials of 566C80, call 1-800-874-2572.
566C80 for Toxoplasmosis
In addition to its potential as a potent anti-PCP agent,
566C80 also has shown strong activity against toxoplasmic
encephalitis in mice. An oral dose of 100 mg/kg/day for 10 days
protected 100% of mice against death from infection with 6
different strains of Toxoplasma gondii, the microorganism that
causes toxoplasmosis, including the most virulent strain (RH).
The NIAID is now recruiting for a safety and efficacy trial of
the drug for PWA with toxoplasmic encephalitis who cannot
tolerate or who have failed 011 standard therapy for the disease.
Conventional treatment for toxoplasmosis is pyrimethamine in
combination with sulfadiazine, a regimen that can cause adverse
side effects, including bone marrow suppression and a severe skin
rash. If left untreated, infection with Toxoplasma gondii may
lead to seizures, coma and death.
Researchers have developed a new laboratory method for
evaluating treatments for the cyst form of Toxoplasma gondii and
have used it to examine 6 drugs: pyrimethamine, sulphadiazine,
5-fluorouracil, clindamycin, azithromycin and 566C80. Cysts were
treated with all 6 drugs separately for 1 - 3 days, then injected
into mice.
Only those mice treated with 566C80 survived. No cysts were
found in the brains of these mice and their blood tested negative
for Toxoplasma gondii. These laboratory data suggest that 566C80
may work as a prophylactic treatment for toxoplasmosis, as well
as a therapy for the acute form of the disease.
Trimetrexate for PCP
and Toxoplasmosis
Trimetrexate was originally developed as an anti-cancer agent.
More recently, the drug has been available in combination with
leucoverin as a salvage treatment for PCP in people who fail on
standard treatments: TMP-SMX (Septra, Bactrim), pentamidine or
Dapsone. Physicians may call 1-800-537-9978 for information
about enrolling patients in a Treatment Investigational New Drug
Protocol (Treatment IND).
The U. S. government recently ; awarded exclusive patent
rights for trimetrexate to U. S. Bioscience, Inc., which plans to
apply for a New Drug Application (NDA) early this year for the
treatment of PCP. In laboratory studies, trimetrexate has also
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shown activity against Toxoplasma gondii, the organism that
causes toxoplasmosis.
GM-CSF Near
FDA Approval
An FDA advisory committee has recommended approval for
granulocyte macrophage-colony stimulating factors (GM-CSF)
produced by 3 different companies. These immunomodulating drugs,
developed by Amgen, Immunex and Hoechst-Roussel Pharmaceuticals,
increase the number of white blood cells that the body uses to
fight off infections. The availability of GM-CSF following FDA
approval will be extremely helpful to cancer patients undergoing
chemotherapy, surgery or bone marrow transplants and to PWA with
depleted white blood cell counts resulting from AZT use.
These immunomodulating drugs are expensive: U. S. sales are
expected to reach $400 million a year within 3 years. Sales
worldwide may reach $1 billion annually, according to some
analysts. FDA approval means that many insurance carriers will
pay for at least part of the drugs' cost.
The FDA has also approved Ortho Biotech's Procrit~'
(erythropoietin), a genetically engineered form of a natural
hormone that helps to reverse anemia in some PWA. The cost of the
drug for a person with AZT-related anemia is high, perhaps $6,000
$8,500 a year for many patients.
T-Helper Cell and
Beta-2 Levels as
Markers of Survival
UCSF researchers have determined that 2 blood markers, T-
helper cell count and beta-2 microglobulin level, are currently
the most reliable indicators of long-term survival. These 2
important blood markers may also help to evaluate the
effectiveness of antiviral treatments like AZT or ddC before an
individual develops AIDS.
The researchers studied 5 markers in 90 people with AIDS or
ARC who were taking AZT: T-helper count, beta-2 microglobulin,
p24 antigen, p24 antibody and neopterin. Although scientists
have previously studied the effect of AZT on all 5 markers, no
one had yet examined which marker changes are linked to long-term
survival.
The researchers discovered that 3 of these markers p24
antigen, p24 antibody and neopterin were 'in-reliable predictors
of longevity.
T-helper cells (CD4 or T4 cells) are critically important to
helping the body fight off infections. They are also a major
target for HIV. As the virus kills or disables T-helper cells,
their number drops, the individual's immune system weakens, and
HIV disease progresses. People in the recent UCSF study taking
AZT for 2-3 months whose T-helper count stayed at or above 100
had a significantly longer life expectancy than those whose count
fell below 100.
Beta-2 microglobulin is a protein produced by interferon in
the body. Interferon is produced in response to viruses such as
HIV or CMV (cytomegalovirus). Laboratories measure beta-2 micro-
globulin in milligrams per liter of blood (mg/1). Researchers
regard levels below 3 mg/1 (simply referred to as 3) as normal in
healthy individuals. When the beta-2 microglobulin rises above
3, the risk for HIV disease progression increases.
The p24 antigen test measures the amount of a protein
component of HIV. Researchers currently use the p24 antigen test
as a marker of how well an antiviral like AZT, ddC or ddI is
working. In the UCSF study, however, investigators found that
p24 antigen was not a good predictor of survival rate in
patients.
The p24 antibody test measures the amount of antibody the body
has produced against the HIV p24 antigen. People in early stages
of HIV disease usually have detectable levels of p24 antibody in
their blood, whereas people with AIDS generally do not have
detectable levels of this antibody.
The most significant practical application of the UCSF study
is that the effectiveness of drugs like AZT, ddC and ddI can be
determined more rapidly using the 2 markers shown to be reliable
predictors of survival rates. Any drug that helps maintain or
increase T-helper cell levels and reduces beta-2 levels might
also be expected to increase life expectancy. New drugs could be
moved through the testing and approval process more quickly if
these 2 markers are accepted as reliable.
Autologous CD8+
Infusion
This therapy consists of isolating CD8+ T-lymphocytes (T-
suppressor cells) from an HIV infected person, then stimulating
these cells to replicate outside the body by using cell-
activating proteins. The increased number of CD8+ cells are then
reinfused into the patient. The rationale for this treatment
rests on laboratory studies that show CD8+ cells can suppress HIv
in the blood cells of PWA.
Four people have enrolled in a 6-month ACTG Phase I dose-
ranging study of autologous CD8+ infusion plus interleukin-2
(IL-2) infusion at the University of Pittsburgh. IL-2 is an
immuno-modulating drug that produces a proliferation and
expansion of activated T-lymphocytes (white blood cells). The
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first person to complete the protocol gained weight and reported
increased energy and sense of well-being. No toxicities have
been reported, except for flu-like symptoms during the IL-2
infusion.
Sandostatin for HIV-Related Diarrhea
Twenty U. S. trial sites will evaluate the effectiveness of
Sandostatin (octreotide acetate) in managing HIV-related
diarrhea. The drug is already used to control diarrhea in cancer
patients with intestinal tumors. Treatment with Sandostatin in
these patients has resulted in weight gain and restoration of
electrolyte balance. The drug's effect on HIV-related diarrhea
is unknown.
Two different clinical trials will test the effectiveness of
the drug in 200 PWA whose diarrhea has not been controlled by
other treatments. The first trial (4 weeks) is a dose ranging
study that also will determine how many PWA with significant
diarrhea respond to Sandostatin. Patients will self-administer
the drug by subcutaneous injection.
The second trial will determine the relapse rate, if any,
among people enrolled in the earlier trial who responded to
treatment with Sandostatin. For information about trial sites
and entry criteria, call Sandoz Pharmaceuticals' toll-free
hotline at 1-800-732-8096, Monday - Friday, 9 AM - 5PM Eastern
Standard Time.
Sandostatin is a synthetic form of somatostatin, a naturally
occurring hormone found in the brain, gastrointestinal tract and
other organs. Like somatostatin, Sandostatin inhibits bowel
secretions that can cause diarrhea. However, the drug is more
potent and longer acting than the natural hormone, according to
Sandoz officials.
HIV-related diarrhea can be caused by a variety of organisms,
including parasites, bacteria and viruses. Cytomegalovirus
(CMV), Mycobacterium avium intercellulare (MAI or MAC) and
cryptosporidium can cause severe diarrhea and wasting. These
infections are also often unresponsive to conventional
treatments. HIV specialists are anxious to find effective
therapies to prevent diarrhea that produces significant weight
loss and weakened nutritional status in people with HIV disease.
Bleomycin for Kaposi's Sarcoma
Bleomycin, a chemicotherapeutic drug, appears to be a safe and
reasonably effective treatment for HIV-related Kaposi's sarcoma
(KS). In a recent study, 60 people with KS associated with
systemic symptoms and/or T-helper cell counts below 400 received
either intramuscular bleomycin (5 mg/day for 3 days every 2 or 3
weeks) or intravenous infusion of the drug (6 mg/m3/day for4 days
every 4 weeks). There were 30 people in each treatment group.
Twenty-nine patients (48.3%) showed a partial response to
treatment as early as the first course of treatment and 20 of
them had responses that lasted 8 to 56 weeks. The mean duration
of therapy was 5 months. Thirteen patients showed no benefit
from the bleomycin treatment. Before developing KS, 8 of these
13 people were diagnosed with toxoplasmosis and treated with
pyoplasmosis rimethamine and sulfadiazine, a regimen that may
have adversely affected their response to bleomycin.
The researchers conclude that bleomycin causes minimal side
effects at the doses studied and produces a greater response rate
for KS than alpha interferon used alone or in combination. Based
on their experience in this study, the investigators recommend
intramuscular injection over I. V. infusion of bleomycin, since
the former is more convenient and less costly than the latter and
produces the same response rate.
Condylox for External
Genital Warts
The FDA has approved Condylox, a topical solution of .5%
podofilox, for treatment of genital warts. The new drug is the
only patient-applied therapy available for this sexually
transmitted disease. Human papilloma virus (HPV), the virus that
causes genital warts, may also play a role in the development of
cervical cancer in women.
Patients apply Condylox 2 times a day for 3 days, then stop
treatment for 4 days. Genital warts often recur, despite
treatment with Condylox or other agents, necessitating repeated
treatment regimens.
There are no data comparing the effectiveness of Condylox to
other therapies for genital warts, such as laser surgery,
cryosurgery (freezing) or injection with alpha interferon. All
these treatments must be performed by trained personnel in a
physician's office or clinic.
Doxycycline for Chlamydial Infections
Monodox, a new oral form of the antibiotic doxycycline, has
been approved for treatment of chlamydia, the most common
sexually transmitted disease (STD) in the U. S. Left untreated,
chlamydia may cause infertility in women with the infection.
Studies of Monodox by its manufacturer, Oclassen Pharmaceuticals,
suggest the drug produces fewer side effects than other currently
available treatments for chlamydial infections.
Clotrimazole for Vaginal Candidiasis
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Gyne-Lotrimin (clotrimazole) has been approved as an over-the-
counter drug for the treatment of vaginal candidiasis, an
infection that can occur in women who are HIV positive or HIV
negative. In women who are HIV negative, vaginal candidiasis may
result from a variety of causes, including pregnancy, the use of
antibiotics or oral contraceptives. Among women who are HIV
positive, this fungal infection may occur as a result of the
immunosuppression caused by HIV infection.
Gyne-Lotrimin is the first over-the-counter medication
approved by the FDA to treat vaginal candidiasis. It became
available as a prescription drug in 1978.
Peridex as Prophylaxis for
Oral Candidiasis
Researchers are actively recruiting patients for a multicenter
trial to evaluate the effectiveness of Peridex rinse in
preventing or delaying oral candidiasis (thrush) in people with
HIV disease. To be eligible, patients must have had clinically
diagnosed oral candidiasis within the last 3 months. This is a
6-month, Phase III trial. In San Francisco, call Dr. Caroline
Dodd at UCSF (415-476-1690). For other trial locations,
telephone 1-800-874-2574, the toll-free hotline for clinical
trials information.
The active ingredient in Peridex is chlorhexidene gluconate,
an antimicrobial agent that has been studied for over 20 years by
its manufacturer, Procter and Gamble. Peridex is currently an
approved drug, available by prescription, for the treatment of
gingivitis and periodontitis. In laboratory studies,
chlorhexidine shows strong activity against Candida albicans, the
fungus that causes oral candidiasis. If left untreated, the
disease frequently prevents patients from eating, drinking or
taking oral drugs easily. This, in turn, may lead to other
problems for the patient.
Oral Alpha Interferon
A 4-month observational study of low-dose oral alpha
interferon shows no statistically significant changes in T-
helper cell counts among 167 people. SEARCH Alliance, a
community based research group in Los Angeles, conducted the
study. The group did not use Kemron, the form of the drug used
in the African study that generated so much attention last year
(BETA, April 1990).
About 25% of the volunteers in the Los Angeles study had a 10%
increase in their baseline T-helper counts, but this increase is
not considered statistically significant. There were also no
significant changes in the participants' p24 antigen levels. No
toxic side effects were reported by any study subjects.
This was not a controlled trial with standardized dosing or a
placebo arm. Although the study results cannot be relied upon as
proof that low-dose oral alpha interferon is ineffective against
HIV, it does offer valuable, practical information about the
drug's action in 167 people over a 16-week period. For more
information about the SEARCH study, send a self-addressed
envelope and a request to SEARCH Alliance, 7461 Beverly Blvd,
Suite 304, Los Angeles, CA 90036.
There are 2 ongoing studies of low-dose oral alpha interferon
at Mt. Sinai Medical Center in New York.
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Take Care,
John
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